Drug delivery across the skin of a patient obviates a variety of problems associated with oral administration of the drug, for example, nausea or vomiting, drug inactivation by gastrointestinal enzymes, and fluctuations in blood concentrations of the drug resulting from fluctuations in absorption from the gastrointestinal tract, and from hepatic first pass inactivation. Drug delivery across the skin of a patient also avoids the inconvenience associated with drug injection.
Transdermal drug delivery has been tackled using one of the two complementary approaches known in the art. One approach utilizes a method of puncturing the skin or otherwise disrupting the impermeable layers of the skin to facilitate the entry of drugs into the systemic circulation, and the other approach provides formulations of drugs that may be applied to the skin in the form of patches, films or matrices of varying compositions.
Transdermal Delivery Apparatus
Electrotransport or iontophoretic drug delivery devices have been disclosed as being useful for the delivery of many types of drugs for which it is anticipated that transdermal delivery would be advantageous. U.S. Pat. Nos. 6,169,920 and 6,317,629 to Alza for example disclose iontophoretic drug delivery apparatus, and U.S. Pat. No. 5,983,130 to Alza discloses an electrotransport agent delivery method and apparatus suitable for ionizable drugs.
Electroporation is also well known in the art as a method to increase pore size by application of an electric field. Electroporation is disclosed as a means for transiently decreasing the electrical resistance of the stratum corneum and increasing the transdermal flux of small molecules by applying an electric field to increase the size of existing pores (Chizmadzhev et al., Biophysics Journal, 1998,74 (2), 843-856).
U.S. Pat. No. 5,019,034 to Weaver et al. describes apparatus for applying high voltage, short duration electrical pulses on the skin to produce electroporation.
WO 97/07734 to Eppstein et al. discloses thermal ablation of the stratum corneum using an electrically resistive element in contact with the stratum corneum, such that a high current through the element causes a general heating of tissue in its vicinity, most particularly the stratum corneum, that is the 10-50 micron thick outermost layer of the skin.
U.S. Pat. Nos. 5,885,211, 6,022,316, 6,142,939 and 6,173,202 to Eppstein et al., which are incorporated herein by reference, describe methods for forming micro-pores in the stratum corneum by heating tissue-bound water above the vapor point with a heat-conducting element, so as to enhance transdermal transport of an analyte or active substance. Further enhancement techniques include the use of sonic energy, pressure, and chemical enhancers.
U.S. Pat. No. 3,964,482 to Gerstel, U.S. Pat. No. 6,050,988 to Zuck, and U.S. Pat. No. 6,083,196 to Trautman et al. describe other apparatus and methods for facilitating transdermal movement of a substance.
U.S. Pat. No. 6,148,232 to Avrahami, which is incorporated herein in its entirety by reference, describes a device for ablating the stratum corneum of a subject. The device includes a plurality of electrodes, which are applied at respective points on skin of a subject. A power source applies electrical energy between two or more of the electrodes to cause ablation of distinct regions of the stratum corneum (SC), primarily beneath the respective electrodes. Various techniques for limiting ablation to the stratum corneum are described, including spacing of the electrodes and monitoring the electrical resistance of skin between adjacent electrodes. The device disclosed in U.S. Pat. No. 6,148,232 and continuations thereto (U.S. Pat. Nos. 5,983,135; 6,579,946; and 6,611,706, and International Patent Applications Nos. WO 01/85234, WO 02/085451 and WO 02/092163 are referred hereinafter in the specification by the name ViaDerm.
Transdermal Patches
There are two prevalent types of transdermal patch designs, namely the reservoir type where the drug is contained within a reservoir having a basal surface that is permeable to the drug, and a matrix type, where the drug is dispersed in a polymer layer affixed to the skin. Both types of designs also typically include a backing layer and an inner release liner layer that is removed prior to use.
Patches usually comprise penetration enhancers and adhesive layers, which known to cause irritation or edema. In addition, patches are known to produce non-uniform rates of drug release between different patients and different skin types.
U.S. Pat. No. 4,668,232 describes a matrix for a transdermal patch, which comprises a reservoir layer comprising a water-swellable polymeric matrix composed of an adhesive material, and a drug that is partially or wholly soluble in the adhesive material. The inclusion of the water-swellable polymer is alleged to increase the release rate of the drug from the matrix.
U.S. Pat. No. 5,230,898 describes a transdermal patch comprising a matrix composed of a water-insoluble material that contains islands of solid particles of a drug in a water-soluble/swellable polymer and an underlayer that controls the amount of water vapor passing from the skin to the matrix. The matrix is said to be activated by water vapor from the skin.
U.S. Pat. No. 4,559,222 describes a transdermal matrix-type patch in which the matrix is composed of a mixture of mineral oil, polyisobutylene (an adhesive), and colloidal silicon dioxide. The addition of the silicon dioxide allegedly affects the flow characteristics of the mineral oil-polyisobutylene mix.
Compositions or devices in the form of specific types of patches adapted for the transdermal delivery of anti-emetics include: U.S. Pat. No. 5,989,586 that discloses a transdermal patch comprising two-phase drug-containing matrix for sustained release of the drug; WO 00/47208 that discloses a transdermal composition comprising a matrix containing an alcohol, a penetration enhancer, water, and an anti-vomiting agent selected from tropisetron, ondansetron and granisetron; and WO 98/53815 that discloses a transdermal delivery device for the delivery of tropisetron or granisetron comprising an adhesive layer comprising specific alkylacrylates and hydrophilic monomers.
There remains an unmet medical need to overcome skin trauma, pain and uncontrollable delivery rate encountered with patches known in the art, and to provide a transdermal delivery system for hydrophilic drugs, which enables increased drug efficacy and sustained activity.